Hasumi Koichi, Sato Shuichiro, Saito Takahisa, Kato Jun-ya, Shirota Kazuhiko, Sato Jun, Suzuki Hiroyuki, Ohta Shuji
Synthetic Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
Pharmacokinetics Research Department, ASKA Pharmaceutical Co., Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
Bioorg Med Chem. 2014 Aug 1;22(15):4162-76. doi: 10.1016/j.bmc.2014.05.045. Epub 2014 Jun 3.
Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after. We have designed isoxazole derivatives through the addition of a fresh interacting fourth site to the structure of the prototypical p38 MAP kinase inhibitor that harbors three point interactive sites. The derivative 26d (AKP-001) shows excellent p38 MAP kinase inhibitory activity and a high selectivity for various kinases. Its rapid metabolism has been confirmed in rats. Moreover, 26d has been shown to be effective in animal models of inflammatory bowel disease.
p38丝裂原活化蛋白（MAP）激酶抑制剂与炎性细胞因子的产生密切相关，被认为是治疗慢性炎症性疾病的有前景的药物。然而，人们也越来越关注其全身性副作用。为了减少副作用的发生，我们鉴定出一种新型p38 MAP激酶抑制剂，它具有前药的特性，仅在炎症部位发挥作用，随后代谢失活。我们通过在具有三个位点相互作用的原型p38 MAP激酶抑制剂结构上添加一个新的相互作用的第四位点，设计了异恶唑衍生物。衍生物26d（AKP-001）显示出优异的p38 MAP激酶抑制活性和对各种激酶的高选择性。已在大鼠中证实其快速代谢。此外，26d已被证明在炎症性肠病动物模型中有效。
